It is known that low density lipoprotein (LDL) particles are important factors in the regulation of plasma cholesterol. The cholesterol is transmitted as either of two types of liquids: (1) triglycerides of cholesterol or (2) long chain fatty acid esters of cholesterol. The LDL particles are small blood-borne lipid encased spheres which ordinarily contain a cholesterol ester as a hydrophobic core. The surface of the LDL particles is composed of certain phospholipids, free cholesterol and apoproteins which direct the particle to the site of metabolism (Regulation of Plasma Cholesterol by Lipoprotein Receptors, Brown et al., Science, Vol. 212, p. 628,, May 8, 1981.
It is also known prior to the present invention that LDL particles ca be broken open to remove the contents and then reconstituted with different materials incorporated into the core of the LDL particles. This reconstitution with different core material does not always provide stable LDL particles but in some instances provides LDL particles which give up the core material before arriving at the intended site. In an ideal situation, the reconstituted LDL particles incorporating the desired material are targeted to the cells and taken up by the cells by endocytosis whereupon the core material is released into the target cell. In this connection, certain cancer cells have extremely high requirements for LDL compared to normal body cells.
One of the objects of the present invention is to provide new compounds which are effective as cytotoxic agents.
Another object is to provide compounds which are readily incorporated into the core of LDL particles and which are stable until incorporated into the target cells.
A still further object is the provision of non-toxic derivative of a steroid compound and a cytotoxic agent which is readily hydrolyzed intracellularly thereby providing a killing dose of the cytotoxic agent within the target cells. These and other objects are accomplished by applicants' discovery which is described in greater detail hereinbelow.